Substituted 6-membered N-heterocyclic compounds and method for their use as neurological regulator

ABSTRACT

This invention relates to substituted 6-membered N-Herterocyclic neurotrophic compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof, wherein R 1 , R 2 , X, Y, and Z are as defined in the description; their preparation methods, compositions comprising the same, and their use as inhibitors of FK560 binding proteases activity for treating and preventing neurodegenerative diseases and other nerve disorders associated with nerve injuries or other related diseases

This application is a PCT application, PCT/CN02/00871, which was filedon Dec. 5, 2002, and claims the priority date of Dec. 6, 2001 in P.R.China.

FIELD OF THE INVENTION

This invention relates to substituted 6-membered N-Herterocycliccompounds, their preparation methods, compositions comprising the same,and their use as inhibitors of FK560 binding proteins (FKBPs) enzymeactivity for treating and preventing neurodegenerative diseases andother nerve disorders associated with nerve injury or other relateddiseases.

BACKGROUND OF THE RELATED ART

Neurodegenerative disease is a kind of progressive disease associatedwith age including, for example, Alzheimer's disease, Parkinson'sdisease, Huntington's disease and amyotrophic lateral sclerosis (ALS).At present there are no effective methods for treating this kind ofdisease due to its unclear mechanism and complicated invasion cause.

As very important biological active molecules existed in the nervesystem, neurotrophic factors (NTFs), such as nerve growth factor (NGF),can effectively promote regeneration and functional recovery of injuredneuraxon. So, neurotrophic factors are considered as a potential drugfor treating neurodegenerative diseases. However, effective clinicalapplication of such neurotrophic molecules is restricted due to theinsurmountable low bioavailability and specificity of large proteinmolecules.

In addition to the immunity system, FKBPs have been found to be presentat high concentrations in the central nervous system. It has been foundthat the immunosuppressant FK506, as a potent inhibitor of FKBPs, canremarkably promote the neurite outgrowth and the nerve fiberdifferentiation, and show excellent blood-brain barrier penetrabilityand bioavailability^([4]). However, when administered chronically, theimmunosuppressant FK506 induces a number of potential side and toxicactions, including nephrotoxicity, such as impairment of glomerularfiltration and irreversible interstitial fibrosis; and neurologicaldeficits, such as involuntary tremors and non-specific cerebral angina.

OBJECT OF THE INVENTION

The object of the present invention is to provide non-immunosuppressivesmall molecule compounds acting on FKBPs for promoting the nerveoutgrowth and regeneration in various neuropathological situationsincluding neurological diseases associated with neurodegeneration, suchas Alzheimer's disease, Parkinson's disease and amyotrophic lateralsclerosis, and neurological disorders caused by various physicalinjuries (such as mechanical injuries or concussions) or other diseases(such as diabetes or autoimmune acquired diseases).

BRIEF DESCRIPTION OF THE INVENTION

It has been found that the compound of formula (I) may be used as FKBPsfor promoting the nerve outgrowth and regeneration in variousneuropathological situations. Thus, the compound of formula (I) could beused to prevent and/or treat neurological diseases associated withneurodegeneration.

In the first aspect, the present invention relates to a compound offormula (I):

or a pharmaceutically acceptable salt or a hydrate thereof, wherein:

X is CH₂, O, S, SO, SO₂ or NR₃, wherein R₃ is hydrogen or C₁-C₃ alkyl;

Y is O or S;

Z is CH₂, O or NR₄, wherein R₄ is hydrogen or C₁-C₆ alkyl;

R₁ is straight or branched chain C₁-C₈ alkyl, straight or branched chainC₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinalkyl or alkenyl chain may be unsubstituted or substituted with one ormore of the following groups: C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₂;

R₂ is straight or branched chain C₁-C₁₀ alkyl, straight or branchedchain C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₁,wherein alkyl or alkenyl chain may be unsubstituted or substituted withone or more of the following groups: C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₂, in addition, wherein a part of carbon atoms ofalkyl or alkenyl can be replaced by nitrogen or oxygen atoms;

Ar₁ and Ar₂ are independently selected from mono-, di-, or tricyclicaromatic carbocyclic ring and heterocyclic ring containing 1 to 6heteroatoms selected from a group consisting of O, S and N, wherein eachsingle ring is 5-membered or 6-membered, and said ring may beunsubstituted or substituted in one to five position(s) with 1 to 3following groups: halogens, nitro, hydroxy, hydroxymethyl,trifluoromethyl, trifluoromethoxyl, straight or branched chain C₁-C₆alkyl, straight or branched chain C₂-C₆ alkenyl, C₁-C₄ alkoxy, C₂-C₄alkenoxy, phenoxy, benzyloxy, carboxyl or amino,

wherein the relative configuration of group —SO₂Ar₁ to group —COZR₂ is atrans-configuration.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising at least one compound of formula (I) or apharmaceutically acceptable salt or a solvate thereof, andpharmaceutically acceptable carriers or excipients.

In a further aspect, the present invention relates to the a method ofpreparing a compound of formula (I) or a pharmaceutically acceptablesalt or a solvate thereof, comprising:

(i) reacting compound 1 with epoxy ethane to obtain compound 2,

(ii) dissolving compound 2 in hydrochloric acid to obtain compound 3,

(iii) dissolving compound 3 in methanol and passing thereinto dry HClgas to obtain compound 4,

(iv) reacting compound 4 with bases in polar non-protonic solvents, andthen undergoing cyclization in the solution of HCl in ethyl ethyl orethanol to obtain compound 5,

(v) reacting compound 5 with R₁COCl to obtain compound 6,

(vi) reacting compound 6 with alkali metal hydroxides to obtain compound7,

(vii) reacting compound 7 with R₂OH or amino acid ester hydrochlorid,DCC, DMAP or TEA to obtain the compound 8, and

(viii) oxidizing compound 7 with MCPBA to obtain the compound of formula(I).

If desired, the obtained compound of formula (I) can be converted to apharmaceutically acceptable salt using a suitable acid or base.

In a still further aspect, the present invention relates to the use ofat least one compound of formula (I) or a pharmaceutically acceptablesalt or a hydrate thereof in preparing a drug for treating and/orpreventing diseases associated with nerve pathological changes.

The present invention also relates to a method for preventing and/ortreating diseases associated with nerve pathological changes comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or a hydrate thereofto the patients in need.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows photomicrographs of chick embryo dorsal root ganglioncultures after incubation with the illustrative compound of Example 4.

FIG. 2 shows an X-ray diffraction structure diagram of the composite000308-FKBP12.

FIG. 3 shows a graph indicating the effect of the representativecompound of Example 4 on the amount of rcsidual noradrenaline (NE) inthe submaxillary glands of mice whose sympathetic nerve terminals aredamaged with 6-OHDA.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, a preferred embodiment is the compound offormula (I), or a pharmaceutically acceptable salt or a hydrate thereof:

X is S, SO, or SO₂;

Y is O;

Z is O or NH,

R₁ is aromatic group Ar₁;

R₂ is selected from the group consisting of straight or branched chainC₁-C₁₀ alkyl, straight or branched chain C₂-C₁₀ alkenyl, C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, and Ar₁, wherein alkyl or alkenyl chainmay be unsubstituted or substituted with one or more of the followinggroups: C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₂, in addition,wherein a part of carbon atoms of alkyl or alkenyl can be replaced bynitrogen or oxygen atoms;

Ar₁ and Ar₂ are independently selected from a cyclic or fused cyclicring and includes a mono-, bi-or tricyclic, carbo-or hetercyclic ring,wherein a ring is consisted by 5-6 elements, the heteroatom consistingof heterocyclic is selected from nitrogen, sulfur or oxygen; wherein thering is either unsubstituted or substituted in one to five position(s)with halo, nitro, hydroxyl, hydoxylmethyl, trifluoromethyl,trifluoromethoxyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alyoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, carboxyl and amino,

wherein the relative configuration of group —SO₂Ar₁ to group —COZR₂ is atrans-configuration.

Preferred compounds or their pharmaceutically acceptable salts orhydrates of the invention include:

-   2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-phenyl-propionic    acid benzyl ester,-   2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-methyl-butyric    acid benzyl ester,-   2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoic    acid benzyl ester,-   2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoic    acid ethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [3-(pyridin-3-yl)]-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [N-methyl-N-(pyridin-2-yl)]-ethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    phenylpropyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (2-trifluoromethyl)-phenylethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (N-methyl-N-benzyl)-ethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (3-phenyl)-allyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (3-cyclohexyl)-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (1,3-diphenyl)-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (1-p-methoxyphenyl-3-phenyl)-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (1-p-fluorophenyl-3-phenyl)-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [3-phenyl-1-(thiophen-2-yl)]-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [3-(6-methyl-pyridin-2-yl)]-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [N-ethyl-N-3-(3-methyl)phenyl]-ethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (1,3-diphenylmethyloxy)-isopropyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (thiophen-2-yl)-ethyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (3-phenoxy)-propyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [1-phenyl-1-(3-tolyl)]-methyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    [1-methyl-1-(3-trifluoromethylphenyl)]-methyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    4-nitrobenzyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    2-methoxybenzyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    (3-ethoxy-2-methoxy)-benzyl ester,-   (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid    4-phenylbenzyl ester, and-   2-{[(3R)-1,1-dioxo-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoic    acid ethyl ester.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids or inorganic or organic bases.Such acid salts include, but are not limited to, the following salts:hydrochloride, hydrobromide, hydriodide, nitrate, sulfate, bisulfate,phosphate, hydrophosphate, acetate, propionate, butanoate, oxalate,trimethyl acetate, adipate, alginate, lactate, citrate, tartrate,succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate,methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate anddihydroxynaphthoate. Such base salts include, but are not limited to,the following salts: ammonium salts, alkali metal salts such as sodiumand potassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts derived from organic bases such asdicyclohexylamine and N-methyl-D-glucamine salts, and salts derived fromamino acids such as arginine and lysine salts.

According to the present invention, the pharmaceutical compositionincludes an effective amount of a compound of formula (I) or apharmaceutical salt or a hydrate thereof, and one or more suitablepharmaceutically acceptable carriers. The pharmaceutically acceptablecarrier is selected from, but is not limited to, the following carriers:ion exchanger, aluminum oxide, aluminum stearate, lecithin, serumprotein (e.g. human serum protein), buffer substance (e.g. phosphate),glycerol, sorbic acid, potassium sorbate, mixture of partial glyceridesof saturated vegetable fatty acids, water, salt or electrolyte (e.g.protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salt), colloidal silicon oxide,magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethyleneglycol, sodium carboxymethycellulose, polyacrylate, beeswax,polyethylene-polyoxopropylene block polymer and lanolin.

The compound of the present invention is a kind of potentneuroregulation molecules having an affinity for FKBPs. In contrast toFK506, the compound of the present invention does not result inimmunosuppression. The neuroregulation activity comprises, but is notlimited to, repair of damaged neurons, promotion of neuronalregeneration, prevention of neurodegeneration and treatment ofneurological disorders associated with neurodegeneration or peripheralnerve pathological changes. The neurological disorders that may betreated include, but are not limited to, Alzheimer's disease,Parkinson's disease, Huntington's disease and amyotrophic lateralsclerosis, nerve pathological changes associated with acquiredimmunodeficiency, cerebrospinal multiple sclerosis, apoplexy or braininjury associated with physical stimulation, various neurodegenerativediseases affecting central or nervous system, cerebellum-brain stematrophy, progressive ataxia syndrome, muscular dystrophy, progressivemuscular atrophy, progressive bulbar inherited muscular atrophy,physical or traumatic injury of central or peripheral nervous system,prolapsed intervertebral disk syndrome, cervical spondylosis, thoracicoutlet destruction syndromes, nerve plexus disorders, thoracic brachialplexus syndrome, various peripheral nerve pathological changes,trigeminal neuralgia, glossopharyngeal neuralgia, facial paralysis,various autoimmune disease which may cause injury of central orperipheral nervous system, myasthenia gravis, Guillain-Barre syndrome,dapsone ticks, bulbar and postbulbar optic nerve pathological changes,retinopathy, postbulbar optic neuritis, audition disorders, or tinnitus.

Among other things, the preferred neurological disorders include, butare not limited to, neurological disorders associated withneurodegeneration such as Alzheimer's disease, Parkinson's disease andamyotrophic lateral sclerosis, and neurological disorders associatedwith peripheral nerve pathological changes, which usually are caused byphysical injuries brain or spinal cord or other associated diseases.

According to the invention, the compound of the present invention may beadministered orally, by inhalation spray, rectally, nasally, buccally,vaginally, topically, parenterally (such as, subcutaneous, intravenous,intramuscular, intraperitoneal, intrachecal, intraventricular,intrasteral, and intracranial injection or infusion techniques), or viaan implanted reservoir, preferably orally, intraperitoneally, orintravenously. In addition, in order to treat central nervous systemdisorders effectively, the compound of the present invention ispreferably administered intraventricularly to overcome possible lowblood-brain barrier penetration of the compound.

When administered orally, the compound of the invention may be producedin any orally acceptable formulation forms comprising, but being notlimited to, tablets, capsules, aqueous solutions or aqueous suspensions.Typically, the carriers used for tablets comprises lactose and cornstarch. In addition, lubricating agents such as magnesium stearate mayalso be added. Usually, the diluents used for capsules comprise lactoseand dried corn starch. Aqueous suspension formulations generallycomprise mixture of suitable emulsifying and suspending agents with theactive ingredient. If desired, the oral formulation forms may furthercomprise sweetening agents, flavoring agents or coloring agents.

The compounds of the invention may also be administered rectally in theform of suppositories. These compositions can be prepared by mixing thedrug with a suitable non-irritating excipient which is solid at roomtemperature, but liquid at rectal temperature and, therefore, will meltin the rectum to release the drug. Such materials include cocoa butter,beeswax and polyethylene glycols.

The compounds of this invention may also be administered topically,especially when the conditions addressed for treatment involve areas ororgans readily accessible by topical application, including neurologicaldisorders of the eye, the skin, or the lower intestinal tract. Thecompounds of the invention may be prepared into different topicaladministration formulations in accordance with the areas or organs.

For topical application to eyes, the compounds of the invention can beformulated as micronized suspensions or solutions in isotonic, pHadjusted sterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for the ophthalmic uses, thecompounds may be formulated in an ointment such as petrolatum.

For topical application to the skin, the compounds can be formulated ina suitable ointment, lotion or cream wherein the active ingredientsuspends or dissolves in one or more carriers. For example, the carrierssuitable for ointment comprise mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylene,emulsifying wax and water; and the carriers suitable for lotion or creamcomprise mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation.

The compounds of the present invention may be administered in the formof sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions. Among the acceptable carriers andsolvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils, such asmono-or di-glycerides, can be also employed as solvents or suspendingmediums.

The compounds can be administered together with other neurotrophicsubstances such as neurotrophic growth factor (NGF), insulin growthfactor (IGF-1), and derived growth factor thereof (gIGF-1), brainderived growth factor(BDGF), glial derived growth factor (GDGF),platelet derived growth factor (PDGF), fibroblast growth factor (aFGFand bFGF), ciliary neurotrophic factor (CNTF), neurotropin-3 (NT-3), andneurotropin-4/5 (NT-4/5), preferably NGF. Such two active ingredientsmay stimulate the growth of nerve synergistically.

It is understood, however, that a specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, rate of excretion, drug combination,and the severity of the particular disease being treated and form ofadministration. Dosage levels on the order of about 0.01 mg to about 100mg of the active ingredient/kg body weight/day are preferred.

The compounds of the present invention were synthesized through thefollowing route:

wherein, Z=O or NH.

The method of the present invention is illustrated as following:

Compound 2 can be obtained by dissolving compound 1 (cysteine, availablefrom ACROS) in a polar solvent (such as water or methanol), andadjusting pH to 7, and then adding epoxy ethane dropwise at atemperature of 0-10° C.;

Compound 3 can be obtained by dissolving compound 2 into concentratedhydrochloric acid and then stirring at 90-95° C.;

Compound 4 can be obtained by dissolving compound 3 in a suitable amountof methanol, and passing dry hydrogen chloride gas in the solution;

Compound 5 can be obtained by dissolving compound 4 in a polarnon-protonic solvent (such as DMF) in the presence of bases at 90-95° C.to give a free amine and then reacting with the solution of HCl in ethylether or ethanol;

Compound 6 can be obtained by dissolving compound 5 in CH₂Cl₂ or THF at0° C. and reacting with the solution of R₁SO₂Cl and triethyl amine inCH₂Cl₂ at room temperature.;

Compound 7 can be obtained by dissolving compound 6 in methanol at 0° C.and reacting with alkali metal hydroxide such as LiOH at roomtemperature;

Compound 8 can be obtained by reacting compound 7, R₂OH, or R₂NH₂, DCC,DMAP, TEA in CH₂Cl₂ or THF at room temperature; and

Compound 9 can be obtained by oxidizing compound 8 with MCPBA in CH₂Cl₂or THF.

EXAMPLES

The following examples are preferred illustrative examples of theinvention and these preferred examples do not intend to limit thepresent invention.

Example 1 Synthesis of2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-phenyl-propionicacid benzyl ester 2-amino-3-(2-hydroxy-ethylsulfanyl)-propionic acid

36.3 g of L-cysteine was dissolved in 300 ml of water. 24 ml 1 mol/L ofNaOH solution was added into above solution and cooled by ice-water bathin order to adjust pH value to 7. And then at 0° C. 30 mL of epoxyethane was added dropwise to the above solution and then mixture wascooled to 10° C. After the mixture was stirred for 1.0 hour, it waswarmed to room temperature and then stirred for 1.5 hours. The resultantmixture was extracted with ethyl ether three times (60 ml, 45 ml, 45 ml)to remove the residual epoxy ethane. Water layer was removed on arot-vap to obtain a buff solid. The solid was recrystallized in 95%ethanol to obtain a white lamellar crystal (33.9 g). Yield 69.4%□mp195-196° C. (Dec.).

¹H-NMR (400 MHz, D₂O): δ 3.96131 (dd, 1H, J₁=4.272 Hz, J₂=7.816 Hz),3.80680-3.77293 (m, 2H), 3.17887 (dd, 1H, J₁=4.268 Hz, J₂=14.814 Hz),3.08224 (dd, 1H, J₁=7.480 Hz, J₂=14.814 Hz), 2.80103 (t, 2H, J=6.036Hz).

2-Amino-3-(2-chloro-ethylsulfanyl)-propionic acid hydrochloride

33.9 g of 2-amino-3-(2-hydroxy-ethylsulfanyl)-propionic acid wasdissolved in 800 mL of concentrated hydrogen chloride and the solutionwas stirred for 7 h to obtain a buff solid. The solid was recrystallizedin isopropanol to obtain a white powder (34.2 g). Yield 75.4%, mp185-186° C.

¹H-NMR (400 MHz, D₂O): δ 6 4.30477-4.26952 (m, 1H), 3.81913-3.78409 (m,2H), 3.25903 (dd, 1H, J₁=4.444 Hz, J₂=14.984 Hz), 3.18877 (dd, 1H, J₁327.352 Hz, J₂=15.072 Hz), 3.04410-3.00625 (m, 2H).

2-Amino-3-(2-chloro-ethylsulfanyl)-propionic acid methyl esterhydrochloride

34.2 g of 2-amino-3-(2-chloro-ethylsulfanyl)-propionic acidhydrochloride was dissolved in 300 mL of absolute methanol (treated withMg) and dry HCl gas (prepared from 250 ml of concentrated sulfuric acidand 200 g of ammonium chloride) was put in the above solution tillsaturation. And then the mixture was stirred for 12 hour and methanolwas removed to obtain 36.3 g white solid. Yield 100%, mp 128-129° C.

¹H-NMR (400 MHz, D₂O): δ 4.45277 (dd, 1H, J₁=4.504 Hz, J₂=7.484 Hz),3.89729 (s, 3), 3.81650-3.77860 (tm, 2H), 3.33808 (dd, 1H, J₁=4.480 Hz,J₂=15.034 Hz), 3.19579 (dd, 1H, J₁=7.500 Hz, J₂=14.992 Hz),3.04047-2.98506 (m, 2H).

(3R)-thiomorpholine-3-carboxylic acid methyl ester

36.3 g of 2-amino-3-(2-chloro-ethylsulfanyl)-propionic acid methyl esterhydrochloride was dissolved in 700 mL of dry DMF in a 100 ml three neckflask and 125 mL of TEA was added dropwise into the above solution. Andthen the mixture was stirred for 8 hours at 90-95° C. The white solidwas removed and the mother liquid was concentrated to obtain a red oil(10.9 g). The obtained red oil was dissolved in ethyl acetate and washedwith saturated aqueous sodium chloride solution (50, 40, 40 ml) and thenwith water (40 ml) and dried over MgSO₄. The drying agent and ethylacetate were removed to obtain a brown oil (10.9 g). Yield 43.6%.

(3R)-thiomorpholine-3-carboxylic acid methyl ester hydrochloride

10.9 g of (3R)-thiomorpholine-3-carboxylic acid methyl ester wasdissolved in 150 mL of ether and 90 mL 14.5% of hydrogen chloridedissolved in ethanol was added dropwise in the above solution to obtain13.0 g of (3R)-thiomorpholine-3-carboxylic acid methyl esterhydrochloride as a white solid. Yield 97.2%□mp 160-161° C.

¹H-NMR (400 MHz, DMSO):δ 10.0898 (brs, 2H),4.4214 (dd, 1H, J₁=3.52 Hz,J₂=8.56 Hz), 3.7833 (s, 3H), 3.4986-3.4766 (m, 1H), 3.2246-3.0606 (m,3H), 2.9897-2.9593 (m, 1H), 2.8763-2.8622 (m, 1H); MS (FAB) m/z: 162.0(M-35.5), 102.0,74.0.

(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid methyl ester

13.0 g of (3R)-thiomorpholine-3-carboxylic acid methyl esterhydrochloride was dissolved in 120 mL of methylene chloride and 30 mL oftriethylamine was added dropwise in the above mixture. After stirringfor 1 h, 13.5 g of p-toluenesulfonyl chloride dissolved in 120 mL ofmethylene chloride was added dropwise into the solution and stirred for24 h at room temperature. The white solid appeared in the process ofreaction was removed by filtration and the mother liquid was washed withsaturated NaHCO₃ and water and dried with Na₂SO₄ overnight. Afterfiltrating and collecting of mother liquid, solvent was distilled and awhite solid was obtained. The solid was recrystallized from ethylacetate and cyclohexane to obtain 19.4 g product as a white crystal.Yield 93.5%□mp 87-88° C.□[α]_(D) ^(24.5)=−78.1° (2.00 g/100 ml, CH₂Cl₂).

¹H-NMR (400 MHz, CDCl₃): δ 7.66938(d, 2H, J=7.352 Hz), 7.29941(d, 2H,J=8.036 Hz), 5.06654 (t, 1H, J=3.436 Hz), 4.04908-3.99999 (m, 1H),3.63087 (s, 3H), 3.45333-3.38197 (m, 1H), 3.06102-3.02157 (m, 1H),3.00305-2.95 904 (m, 1H), 2.82287-2.74967 (m, 1H), 2.42975 (s, 3H),2.40451-2.36514(1H).

(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid

8.3 g of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acidmethyl ester was dissolved in 157 mL of methanol and 52.5 ml 1 mol/L ofLiOH solution was added dropwise in the above solution at 0° C. Themixture was stirred for 48 h and ethyl acetate (60, 60 ml) was addedinto the reaction mixture and separated to collect mother liquid. Themother liquid was acidified by 100 ml 1 mol/L hydrogen chloride toadjust pH value to 2. Filtrated and collected the white solid to obtain7.7 g product. Yield 97.0%□mp149-150° C.

¹H-NMR (400 MHz, CDCl₃): δ 9.87650 (brs, 1H), 7.68301-7.65750 (m, 2H),7.29537(d, 2H, J=8.024 Hz), 5.11555 (t, 1H, J=3.456 Hz), 4.04252-3.99349(m, 1H), 3.47279-3.40112 (m, 1H), 3.06220-2.96007 (m, 2H),2.80470-2.73149 (m, 1H), 2.42613 (s, 3H), 2.38398 (s, 1H).

2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-phenyl-propionicacid benzyl ester

0.602 g (2 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.939 g (2.2mmol) of L-phenylalanine benzyl ester p-toluenesulfonic acid salt, 0.454g (2.2 mmol) of DCC and 0.224 g (2 mmol) of DMAP were dissolved in 30 mLof CH₂Cl₂, 0.4 ml (2.7 mmol) of TEA was added. The mixture was stirredfor 24 h at room temperature. The solid was filtrated and the solventwas evaporated. The residual was dissolved in a suitable amount of ethylacetate (20 ml) and then the mixture was filtered to remove insolublesubstance. The ethyl acetate was added to 60 ml and then the liquid waswashed with 10% NaHCO₃ solution, saturated NaCl solution and dried overNa₂SO₄. After the drying agent was removed and part of ethyl acetate wasevaporated, the crude product was purified by flash columnchromatography (eluent: CH₂Cl₂:CH₃Cl=1:1) to obtain the product as aglassy solid (0.80 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.66072-7.63134 (m, 2H), 7.37633-7.34761 (m,4H), 7.30475-7.28315 (m, 4H), 7.25816-7.18850 (m, 2H), 7.08602-7.06666(m, 2H), 6.92373(d, 0.5H, J=7.092 Hz), 6.83414(d, 0.5H, J=7.092 Hz),5.23479(d, 0.5H, J=12.148 Hz), 5.16985 (dd, 1H, J₁=4.796 Hz, 4.956 Hz,J₂=12.108 Hz), 5.07028(d, 0.5H, J=12.000 Hz), 498245-4.96101 (m, 0.5H),4.84773-4.83241 (m, 0.5H), 4.77844-4.71409 (m, 1H), 3.95856-3.89722 (m,1H), 3.30404 (dd, 0.5H, J₁=5.772 Hz, 5.752 Hz, J₂=13.994 Hz),3.22070-3.01464 (m, 3H), 2.79171-2.71763 (m, 0.5H), 2.54595-2.50159 (m,0.5H), 2.46259-2.39754 (m, 4H), 2.32092 (brs, 0.5H), 2.05599-1.94058 (m,1H); MS (EI) m/z: 539.1, 383.0, 283.9, 255.9, 190.0, 154.9, 120.0, 91.0,65.0.

Example 2 Synthesis of2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-methyl-butyricacid benzyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.417 g (1.1mmol) of L-valine benzyl ester p-toluenesulfonic acid salt, 0.227 g (1.2mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mL ofCH₂Cl₂, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirred for24 h at room temperature. The solid was filtrated and the solvent wasevaporated. The residual was dissolved in a suitable amount of ethylacetate (20 ml) and then the mixture was filtered to remove insolublesubstance. The ethyl acetate was added to 60 ml and then the liquid waswashed with 10% NaHCO₃ solution, saturated NaCl solution and dried overNa₂SO₄. After the drying agent was removed and part of ethyl acetate wasevaporated, the crude product was purified by flash columnchromatography (eluent: CH₂Cl₂:CH₃Cl=1:1) to obtain the product as aglassy solid (0.20 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.7688-7.7235 (m, 2H), 7.3730-7.3271 (m, 7H),6.9956(d, 0.5H, J=9.16 Hz), 6.9125 (d, 0.5H, J=9.16 Hz), 5.2509-5.2109(m, 1H), 5.1697 (m, 1H), 4.7891 (brs, 1H), 4.6640 (dd, 0.5H, J₁=4.44 Hz,4.47 Hz, J₂=9.19 Hz), 4.5986 (dd, 0.5H, J₁=4.58 Hz, J₂=8.59 Hz),4.2220(d, 0.5H, J=14.68 Hz), 4.0949(d, 0.5H, J=14.78 Hz), 3.4084-3.2968(m, 1H), 3.1353(d, 1H, J=12.23 Hz), 5.2997-2.3978 (m, 5H), 2.2581-2.0801(m, 2H), 0.9311 (dd, 3H, J₁=6.84 Hz, 6.86 Hz, J₂=17.51 Hz), 0.8297 (dd,3H, J₁=6.98 Hz, 6.94 Hz, J₂=6.73 Hz); MS (EI) m/z: 491.1, 355.0, 335.0,255.9, 190.0, 154.9, 138.9, 91.0, 65.0.

Example 3 Synthesis of2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid benzyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.432 g (1.1mmol) of L-leucine benzyl ester p-toluenesulfonic acid salt, 0.227 g(1.2 mmol) of DCC and 0.122 g (1 mmol) of DMAP were dissolved in 30 mLof CH₂Cl₂, 0.2 ml (1.4 mmol) of TEA was added. The mixture was stirredfor 24 h at room temperature. The solid was filtrated and the solventwas evaporated. The residual was dissolved in a suitable amount of ethylacetate (20 ml) and then the mixture was filtered to remove insolublesubstance. The ethyl acetate was added to 60 ml and then the liquid waswashed with 10% NaHCO₃ solution, saturated NaCl solution and dried overNa₂SO₄. After the drying agent was removed and part of ethyl acetate wasevaporated, the crude product was purified by flash columnchromatography (eluent: CH₂Cl₂:CH₃Cl=1:1) to obtain the product as a oil(0.48 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.7222(d, 2H, J=8.20 Hz), 7.3910-7.3366 (m,7H), 6.7213(d, 1H, J=8.80 Hz), 5.2003(d, 1H, J=12.16 Hz), 5.0994(d, 1H,J=12.16 Hz), 4.7786-4.7329 (m, 2H), 4.1188(d, 1H, J=14.80 Hz),3.4060-3.3329 (m, 1H), 3.1096(d, 1H, J=13.64 Hz), 2.5188-2.3676 (m, 5H),2.0538(d, 1H, J=13.44 Hz), 1.6967-1.4486 (m, 3H), 0.9175 (d, 3H, J=2.49Hz), 0.9018 (d, 3H, J=2.53 Hz); MS (EI) m/z: 505.4, 368.8, 348.8, 283.9,255.9, 190.0, 155.0, 112.0, 90.0, 65.0.

Example 4 Synthesis of2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid ethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.215 g (1.1mmol) of L-leucine ethyl ester hydrochlorid, 0.227 g (1.2 mmol) of DCCand 0.122 g (1 mmol) of DMAP were dissolved in 30 mL of CH₂Cl₂, 0.2 ml(1.4 mmol) of TEA was added. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:CH₂Cl₂:CH₃Cl=1:1) to obtain the product as a oil (0.36 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.77237-7.74077 (m, 2H), 7.36382(d, 2H,J=7.988 Hz), 6.74090(d, 1H, J=9.244 Hz), 4.80098-4.77466 (m, 1H),4.68244-4.58898 (m, 1H), 4.28174-4.15708 (m, 3H), 3.53789-3.28674 (m,1H), 3.13092 (d, 1H, J=13.676), 2.56954-2.42247 (m, 5H), 2.24620-2.20545(m, 1H), 1.66352-1.53450 (m, 3H), 1.30702-1.26745 (m, 3H),0.96159-0.91891 (m, 6H); MS (EI) m/z: 443.1, 397.1, 369.1, 287.1, 256.0,213.1,155.0, 139.0, 112.0, 91.0, 65.0.

Example 5 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[3-(pyridin-3-yl)]-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.206 g (1.5mmol) of 3-(pyridin-3-yl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:1) to obtain the product as a oil (0.39 g).

¹H-NMR (400 MHz, CDCl₃): δ 8.4699-8.4438 (m, 2H), 7.6702(d, 2H, J=8.24Hz), 7.5056-7.4863 (m, 1H), 7.2847-7.2140 (m, 3H), 5.0708 (t, 1H, J=3.35Hz), 4.1237-4.0851 (m, 2H), 4.0284-3.9869 (m, 1H), 3.4732-3.4018 (m,1H), 3.0225-2.9603 (m, 2H), 2.8096-2.7364 (m, 1H), 2.6714-2.6327 (m,2H), 2.4134-2.3756 (m, 4H), 1.9315-1.8778 (m, 2H); MS (EI) m/z: 421.8,347.3, 265.4, 237.3, 192.3, 155.2, 119.9, 90.9, 64.9.

Example 6 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[N-methyl-N-(pyridin-2-yl)]-ethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.228 g (1.5mmol) of N-methyl-N-(pyridin-2-yl)-ethanol, 0.088 g (0.33 mmol) of CAS,0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolvedin 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:1) to obtain the product as a oil (0.32 g).

¹H-NMR (400 MHz, CDCl₃): δ 8.15202-8.13465 (m, 1H), 7.65765-7.63191 (m,2H), 7.48462-7.44059 (m, 1H), 7.27137-7.25120 (m, 2H), 6.57550 (dd, 1H,J₁=5.088 Hz, 5.352 Hz, J₂=6.864 Hz), 6.49163(d, 1H, J=8.564 Hz), 5.00609(t, 1H, J=3.348 Hz), 4.31854-4.21503 (m, 2H), 3.99180-3.95109 (m, 1H),3.89777-3.84669 (m, 1H), 3.77810-3.72768 (m, 1H), 3.42992-3.35844 (m,1H), 3.03108 (s, 3H), 2.91483(d, 2H, J=3.640 Hz), 2.77988-2.70670 (m,1H), 2.40416 (s, 3H), 2.34020-2.30628 (m, 1H); MS (EI) m/z: 435.0,280.0, 256.0, 154.9, 135.0, 121.0, 107.0, 91.0, 65.0.

Example 7 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid phenylpropylester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.204 g (1.5mmol) of phenylpropanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol)of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH₂Cl₂.The mixture was stirred for 24 h at room temperature. The solid wasfiltrated and the solvent was evaporated. The residual was dissolved ina suitable amount of ethyl acetate (20 ml) and then the mixture wasfiltered to remove insoluble substance. The ethyl acetate was added to60 ml and then the liquid was washed with 10% NaHCO₃ solution, saturatedNaCl solution and dried over Na₂SO₄. After the drying agent was removedand part of ethyl acetate was evaporated, the crude product was purifiedby flash column chromatography (eluent: ethyl acetate:cyclohexane=2:1)to obtain the product as a oil (0.27 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.67345(d, 2H, J=8.324 Hz), 7.31068-7.26240(m, 4H), 7.22238-7.18556 (m, 1H), 7.16516 (m, 2H), 5.06053 (t, 1H,J=3.408 Hz), 4.10609-4.00046 (m, 3H), 3.48604-3.41471 (m, 1H),3.02055-3.00423 (m, 2H), 2.83838-2.76520 (m, 1H), 2.63293 (t, 2H,J=7.452 Hz), 2.41556-2.38244 (m, 4H), 1.91367-1.84295 (m, 2H); MS (EI)m/z: 419.5, 300.5, 255.4, 154.6, 138.7, 116.8, 90.8, 64.9.

Example 8 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(2-trifluoromethyl)-phenylethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.285 g (1.5mmol) of (2-trifluoromethyl)-phenylethanol, 0.088 g (0.33 mmol) of CAS,0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolvedin 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:3) to obtain the product as a oil (0.44 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6631-7.6316 (m, 3H), 7.5113-7.4740 (m, 1H),7.3733-7.2847 (m, 4H), 5.0451 (t, 1H, J=3.38 Hz), 4.3385-4.2132 (m, 2H),4.0266-3.99777 (m, 1H), 3.4194-3.3481 (m, 1H), 3.0712-3.0357 (m, 2H),2.9794-2.9707 (m, 2H), 2.8070-2.7340 (m, 1H), 2.4153 (s, 3H), 2.3575(d,1H, J=13.59 Hz); MS (EI) m/z: 472.9, 399.9, 317.9, 255.8, 172.9, 154.9,132.9, 117.9, 100.9, 64.9.

Example 9 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(N-methyl-N-benzyl)-ethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.275 g (1.5mmol) of (N-methyl-N-benzyl)-ethanol, 0.088 g (0.33 mmol) of CAS, 0.227g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15mL of CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:2) to obtain the product as a oil (0.36 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6627-7.6418 (m, 2H), 7.3460-7.2454 (m, 7H),5.0666 (t, 1H, J=3.40 Hz), 4.2701-4.2416 (m, 2H), 4.0184-3.9844 (m, 1H),3.5281-3.4331 (m, 3H), 3.0252-2.9927 (m, 2H), 2.7929-2.7614 (m, 1H),2.5949 (brs, 2H), 2.4087-2.3563 (m, 4H), 2.2302 (s, 3H); MS (EI) m/z:449.4, 292.9, 255.9, 154.9, 133.8, 90.9, 64.9.

Example 10 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-phenyl)-allyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.200 g (1.5mmol) of (3-phenyl)-allyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:4) to obtain the product as a oil (0.21 g).

¹H-NMR (400MHz, CDCl₃): δ 7.6671(d, 2H, J=8.32 Hz), 7.3832-7.2378 (m,7H), 6.5952(d, 1H, J=15.88 Hz), 6.1464-6.1066 (m, 1H), 5.1104 (t, 1H,J=3.39 Hz), 4.7680-4.7170 (m, 1H), 4.6815-4.6336 (m, 1H), 4.0600-4.0113(m, 1H), 3.4935-3.4223 (m, 1H), 3.1124-3.0724 (m, 1H), 3.0388-2.9948 (m,1H), 2.8503-2.7772 (m, 1H), 2.4238-2.3707 (m, 4H); MS (EI) m/z: 417.0,299.9, 255.9, 154.9, 134.0, 117.0, 108.0, 91.0, 65.0.

Example 11 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-cyclohexyl)-propyl ester,

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.213 g (1.5mmol) of (3-cyclohexyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:4) to obtain the product as a oil (0.33 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6705(d, 2H, J=8.28 Hz), 7.2869(d, 2H,J=8.40 Hz), 5.0506 (t, 1H, J=3.38 Hz), 4.0627-3.9712 (m, 3H),3.4698-3.3986 (m, 1H), 3.0360-3.0058 (m, 2H), 2.8073-2.7996 (m, 1H),2.4237-2.3733 (m, 4H),1.7151-1.6566 (m, 5H), 1.5460-1.5076 (m, 2H),1.2338-1.1368 (m, 6H), 0.8684-0.8380 (m, 2H); MS (EI) m/z: 425.9, 301.8,269.9, 255.8, 154.8, 102.9, 90.9, 69.0.

Example 12 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1,3-diphenyl)-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.318 g (1.5mmol) of (1,3-diphenyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:3) to obtain the product as a oil (0.15 g). ¹H-NMR(400 MHz, CDCl₃): δ 7.5040(d, 2H, J=8.32 Hz), 7.3751-7.0634 (m, 12H),5.7186-5.6846 (m, 1H), 5.0645 (t, 1H, J=3.42 Hz), 4.0136-3.9800 (m, 1H),3.4760-3.4052 (m, 1H), 3.1031-3.0773 (m, 2H), 2.8562-2.7914 (m, 1H),2.6613-2.5414 (m, 2H), 2.4304-2.3855 (m, 1H), 2.3333 (s, 3H),2.2283-2.2041 (m, 1H), 2.0565-2.0328 (m, 1H); MS (EI) m/z: 495.8, 449.8,391.8, 339.8, 299.7, 255.7, 193.8, 154.8, 138.8, 116.9, 90.8, 64.9.

Example 13 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1-p-methoxyphenyl-3-phenyl)-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.242 g (1.0mmol) of (1-p-methoxyphenyl-3-phenyl)-propanol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.20 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.5282(d, 2H, J=8.32 Hz), 7.2780-7.1066 (m,9H), 6.8882(d, 2H, J=6.76 Hz), 5.6898-5.6552 (m, 1H), 5.0336 (t, 1H,J=6.69 Hz), 4.0021-3.9684 (m, 1H), 3.8409 (s, 3H), 3.4592-3.3883 (m,1H), 3.0842-3.0182 (m, 2H), 2.8402-2.7839 (m, 1H), 2.6359-2.5973 (m,1H), 2.5402-2.5160 (m, 1H), 2.4131-2.3527 (m, 4H), 2.2194-2.1947 (m,1H), 2.0300-2.0048 (m, 1H); MS (EI) m/z: 525.6, 392.5, 301.5, 255.6,224.6, 192.7, 177.7, 155.1,121.2, 90.8, 64.9.

Example 14 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1-p-fluorophenyl-3-phenyl)-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.230 g (1.0mmol) of (1-p-fluorophenyl-3-phenyl)-propanol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.39 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6791-7.5152 (m, 2H), 7.2611-7.0466 (m,11H), 5.6948-5.6605 (m, 1H), 5.0412 (t, 1H, J=3.41 Hz), 4.0181-3.9703(m, 1H), 3.4608-3.3958 (m, 1H), 3.0823-3.0528 (m, 2H), 2.8056-2.7655 (m,1H), 2.6484-2.6102 (m, 1H), 2.5565-2.5328 (m, 1H), 2.4185-2.3502 (m,4H), 2.2235-2.1996 (m, 2H); MS (EI) m/z: 513.6, 468.5, 392.1, 358.4,301.7, 255.6, 212.2, 180.8, 154.8, 109.1, 90.9, 64.9.

Example 15 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[3-phenyl-1-(thiophen-2-yl)]-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.218 g (1.0mmol) of 3-phenyl-1-(thiophen-2-yl)-propanol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.37 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.64712-7.57181 (m, 2H), 7.31524-7.13747 (m,8H), 6.99553-6.98669 (m, 2H), 6.03583-6.00112 (m, 1H), 5.04079 (t, 1H,J=3.372 Hz), 4.03332-3.98470 (m, 1H), 3.46631-3.40137 (m, 1H),3.07737-2.97905 (m, 2H), 2.81385-2.80575 (m, 1H), 2.60288-2.57826 (m,2H), 2.40946-2.37125 (m, 4H), 2.28307-2.25916 (m, 1H), 2.15384-2.12909(m, 1H); MS (EI) m/z: 501.0, 392.0, 346.0, 300.0, 256.0, 201.0, 185.0,154.9, 138.9, 110.0, 91.0, 65.0.

Example 16 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[3-(6-methyl-pyridin-2-yl)]-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.230 g (1.5mmol) of 3-(6-methyl-pyridin-2-yl)-propanol, 0.088 g (0.33 mmol) of CAS,0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolvedin 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:1) to obtain the product as a oil (0.23 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6656(d, 2H, J=8.30 Hz,), 7.4728 (t, 1H,J=7.64 Hz), 7.2650(d, 2H, J=8.12 Hz), 6.9460 (dd, 2H, J=7.64 Hz), 5.0402(t, 1H, J=3.36), 4.1435-4.0560 (m, 2H), 4.0394-3.9971 (m, 1H),3.4897-3.45 25 (m, 1H), 3.0141-3.0037 (m, 1H), 2.9842-2.9402 (m, 1H),2.8000-2.7272 (m, 3H), 2.5152 (s, 3H), 2.3985-2.3680 (m, 4H),2.0002-1.9645 (m, 2H); MS (EI) m/z: 435.1, 361.1, 280.1, 256.0,206.1,155.0, 134.0, 120.0, 107.1, 91.0, 77.0, 65.0.

Example 17 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[N-ethyl-N-3-(3-methyl)phenyl]-ethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.290 g (1.5mmol) of N-ethyl-N-3-(3-methyl)phenyl-ethanol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:4) to obtain the product as a oil (0.26 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6328(d, 2H, J=8.64 Hz), 7.2266(d, 2H,J=8.68 Hz), 7.1124-7.0718 (m, 1H), 6.5235-6.4769 (m, 3H), 5.0218 (t,1H,J=3.36 Hz), 4.2291-4.1853 (m, 1H), 4.1530-4.1093 (m, 1H),4.0146-3.9662 (m, 1H), 3.4556-3.4073 (m, 3H), 3.3813-3.3020 (m, 2H),2.9381(d, 2H J=3.68 Hz), 2.7606-2.7020 (m, 1H), 2.6938 (s, 3H),2.3649-2.3449 (m, 1H), 2.0165 (s, 3H), 1.1171 (t, 3H, J=6.98 Hz); MS(EI) m/z: 462.1, 447.0, 255.9, 162.1,148.0, 134.0, 120.0, 101.0, 83.9,65.0.

Example 18 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1,3-diphenylmethyloxy)-isopropyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.420 g (1.5mmol) of (1,3-diphenylmethyloxy)-isopropanol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:6) to obtain the product as a oil (0.50 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6356(d, 2H, J=8.36 Hz), 7.3432-7.2666 (brs,10H), 7.1849(d, 2H, J=8.40 Hz), 5.1879-5.1623 (m, 1H), 5.0965 (t, 1H,J=3.20 Hz), 4.5299-4.4579 (m, 4H), 3.9542-3.9127 (m, 1H) 3.6547-3.6179(m, 1H) 3.5932-3.5497 (m, 3H), 3.5014-3.4300 (m, 1H), 3.0354-3.0247 (m,1H), 2.9998-2.9558 (m, 1H), 2.8109-2.7379 (m, 1H), 2.3696 (s, 3H),2.3139-2.2757 (m, 1H).

Example 19 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(thiophen-2-yl)-ethyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5mmol) of (thiophen-2-yl)-ethanol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:6) to obtain the product as a oil (0.28 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6518(d, 2H, J=6.60 Hz), 7.6601-7.6392 (m,2H).7.1611 (dd, 1H, J₁=7.28 Hz, J₂=0.68 Hz), 6.9325 (dd, 1H, J₌3.50Hz,J₂=5.08 Hz), 6.8210-6.8111 (m, 1H), 5.0563 (t, 1H, J=3.36 Hz),4.3347-4.2140 (m, 2H), 4.0086-3.9596 (m, 1H), 3.4014-3.3301 (m, 1H),3.0775-2.9831 (m, 4H), 2.7804-2.7479 (m, 1H), 2.4220 (s, 3H),2.3687-2.3300 (m, 1H); MS (EI) m/z: 411.1, 256.1, 155.1, 139.1, 110.1,91.1, 77.1, 65.1.

Example 20 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-phenoxy)-propyl ester

0.301 g (1 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5mmol) of (3-phenoxy)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL ofCH₂Cl₂. The mixture was stirred for 24 h at room temperature. The solidwas filtrated and the solvent was evaporated. The residual was dissolvedin a suitable amount of ethyl acetate (20 ml) and then the mixture wasfiltered to remove insoluble substance. The ethyl acetate was added to60 ml and then the liquid was washed with 10% NaHCO₃ solution, saturatedNaCl solution and dried over Na₂SO₄. After the drying agent was removedand part of ethyl acetate was evaporated, the crude product was purifiedby flash column chromatography (eluent: ethyl acetate:cyclohexane=1:4)to obtain the product as a oil (0.39 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6586 (d, 2H, J=8.40 Hz), 7.2822-7.2507 (m,4H) 6.9676-6.9307 (m, 1H). 6.8864-6.8648 (m, 2H).5.0614 (t, 1H, J=3.40Hz), 4.2890-4.2472 (m, 2H), 4.0024-3.9641 (m, 3H), 3.4320-3.3606 (m,1H), 3.0216-2.9506 (m, 2H), 2.8043-2.7313 (m, 1H), 2.4034 (s, 3H),2.3621-2.3239 (m, 1H), 2.0710-2.0223 (m, 2H); MS (EI) m/z: 435.5, 342.4,280.5, 256.4, 227.5, 186.4, 155.3, 139.3, 101.3, 77.2.

Example 21 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[1-phenyl-1-(3-tolyl)]-methyl ester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.196 g (1.0mmol) of 1-phenyl-1-(3-tolyl)-methanol, 0.088 g (0.33 mmol) of CAS,0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolvedin 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.24 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.5729-7.5521 (m, 2H), 7.3578-7.3008 (m, 5H),7.2962-7.2405 (m, 4H), 7.1499-7.1005 (m, 2H), 6.7798(d, 1H, J=3.04 Hz),5.1206 (t, 1H, J=3.40 Hz), 3.9791(d, 1H, J=13.6 Hz), 3.4465-3.4314 (m,1H) 3.1366-3.0893 (m, 1H), 3.0466-3.0023 (m, 1H), 2.8158-2.7431 (m, 1H),2.3658-2.3578 (m, 4H), 2.3177-2.3098 (m, 3H); MS (EI) m/z: 481.5, 300.4,256.4, 181.3, 155.3, 139.3, 115.3, 91.2, 65.2.

Example 22 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[1-methyl-1-(3-trifluoromethylphenyl)]-methyl ester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.0mmol) of 1-methyl-1-(3-trifluoromethylphenyl)-methanol, 0.088 g (0.33mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAPwere dissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h atroom temperature. The solid was filtrated and the solvent wasevaporated. The residual was dissolved in a suitable amount of ethylacetate (20 ml) and then the mixture was filtered to remove insolublesubstance. The ethyl acetate was added to 60 ml and then the liquid waswashed with 10% NaHCO₃ solution, saturated NaCl solution and dried overNa₂SO₄. After the drying agent was removed and part of ethyl acetate wasevaporated, the crude product was purified by flash columnchromatography (eluent: ethyl acetate:cyclohexane=1:9) to obtain theproduct as a oil (0.13 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6060-7.5522 (m, 3H), 7.5157-7.4522 (m, 3H),7.1652(d, 2H, J=8.00 Hz), 5.8728 (dd, 1H, J₁=13.20 Hz, J₂=6.64 Hz),5.0743 (t, 1H, J=3.44 Hz), 4.0359-3.9869 (m, 1H), 3.4477-3.3767 (m, 1H),3.1175-3.0714 (m, 1H), 3.0514-3.0072 (m, 1H), 2.8418-2.7085 (m, 1H),2.4092 (s, 1H), 2.3747 (s, 3H), 1.4918 (d, 3H, J=6.64 Hz); MS (EI) m/z:473.4, 318.4, 300.4, 256.4, 173.4, 155.3, 133.3, 91.3, 65.2.

Example 23 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid 4-nitrobenzylester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.0mmol) of 4-nitrobenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL ofCH₂Cl₂. The mixture was stirred for 24 h at room temperature. The solidwas filtrated and the solvent was evaporated. The residual was dissolvedin a suitable amount of ethyl acetate (20 ml) and then the mixture wasfiltered to remove insoluble substance. The ethyl acetate was added to60 ml and then the liquid was washed with 10% NaHCO₃ solution, saturatedNaCl solution and dried over Na₂SO₄. After the drying agent was removedand part of ethyl acetate was evaporated, the crude product was purifiedby flash column chromatography (eluent: ethyl acetate:cyclohexane=1:9)to obtain the product as a oil (0.29 g).

¹H-NMR (400 MHz, CDCl₃): δ 8.1866(d, 2H, J=8.68 Hz), 7.6521(d, 2H,J=8.68 Hz), 7.4561(d, 2H, J=8.44 Hz), 7.2539(d, 2H, J=8.36 Hz),5.2457-5.2062 (m, 2H), 5.1662 (t, 1H, J=3.6 Hz), 4.0484-3.9997 (m, 1H),3.4650-3.3935 (m, 1H), 3.1092-3.0637 (m, 1H), 3.0133-2.9689 (m, 1H),2.7844-2.7113 (m, 1H), 2.4157-2.3775 (m, 4H); MS (EI) m/z: 437.0, 281.0,256.1,184.0, 154.9, 135.9, 91.0, 65.0.

Example 24 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid2-methoxybenzyl ester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.138 g (1.0mmol) of 2-methoxybenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:6) to obtain the product as a oil (0.19 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6450-7.6152 (m, 2H), 7.3286-7.2851 (m, 1H),7.2068-7.1789 (m, 3H), 6.9372-6.9166 (m, 1H), 6.8642(d, 1H, J=8.16 Hz),5.1842(d, 1H, J=24.1 Hz), 5.1054-5.0535 (m, 2H), 4.0126-3.9637 (m, 1H),3.7975 (s, 3H), 3.5146-3.4432 (m, 1H), 3.0867-3.0412 (m, 1H),3.0026-2.9585 (m, 1H), 2.8240-2.7513 (m, 1H), 2.3782-2.3414 (m, 4H); MS(EI) m/z: 421.0, 300.0, 255.8, 241.0, 211.0, 154.9, 138.9, 121.0, 91.0,65.0.

Example 25 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-ethoxy-2-methoxy)-benzyl ester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.0mmol) of (3-ethoxy-2-methoxy)-benzyl alcohol, 0.088 g (0.33 mmol) ofCAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP weredissolved in 15 mL of CH₂Cl₂. The mixture was stirred for 24 h at roomtemperature. The solid was filtrated and the solvent was evaporated. Theresidual was dissolved in a suitable amount of ethyl acetate (20 ml) andthen the mixture was filtered to remove insoluble substance. The ethylacetate was added to 60 ml and then the liquid was washed with 10%NaHCO₃ solution, saturated NaCl solution and dried over Na₂SO₄. Afterthe drying agent was removed and part of ethyl acetate was evaporated,the crude product was purified by flash column chromatography (eluent:ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.19 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6325(d, 2H, J=8.28 Hz), 7.2212(d, 2H,J=8.24 Hz), 6.8342-6.7827 (m, 3H), 5.6953-5.0652 (m, 2H), 4.9789(d, 1H,J=24.00 Hz), 4.0876 (dd, 2H), J₁=6.99 Hz, J₂=13.99 Hz), 4.0048-3.9569(m, 1H), 3.8465 (s, 3H), 3.4636-3.3924 (m, 1H), 3.0680-3.0339 (m, 1H),2.9730-2.9289 (m, 1H), 2.7775-2.7047 (m, 1H), 2.3920-2.3320 (m, 4H),1.4517 (t, 3H, J=11.00 Hz); MS (EI) m/z: 465.0, 256.0, 165.0, 137.0,101.0, 91.0, 65.0.

Example 26 Synthesis of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid4-phenylbenzyl ester

0.200 g (0.6 mmol) of(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.184 g (1.0mmol) of 4-phenylbenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g(1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mLof CH₂Cl₂. The mixture was stirred for 24 h at room temperature. Thesolid was filtrated and the solvent was evaporated. The residual wasdissolved in a suitable amount of ethyl acetate (20 ml) and then themixture was filtered to remove insoluble substance. The ethyl acetatewas added to 60 ml and then the liquid was washed with 10% NaHCO₃solution, saturated NaCl solution and dried over Na₂SO₄. After thedrying agent was removed and part of ethyl acetate was evaporated, thecrude product was purified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:9) to obtain the product as a oil (0.29 g).

¹H-NMR (400 MHz, CDCl₃): δ 7.6067(d, 2H, J=8.30 Hz), 7.4254-7.3367 (m,6H), 7.3041-7.2364 (m, 3H), 7.1667(d, 2H, J=8.00 Hz), 5.0923-4.9933 (m,3H), 3.9882-3.9393 (m, 1H), 3.4185-3.3471 (m, 1H), 2.9487(d, 2H, J=3.40Hz), 2.7940-2.7210 (m, 1H), 2.3549-2.3195 (m, 4H); MS (EI) m/z: 467.0,422.0, 312.0, 255.9, 167.0, 115.0, 91.0, 65.0.

Example 27 Synthesis of2-{[(3R)-1,1-dioxo-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid ethyl ester

1.0 mmol of2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid ethyl ester was dissolved in 20 ml of CH₂Cl₂, and a solution (10ml) of MCPBA (2 mmol) in CH₂Cl₂. The mixture was stirred roomtemperature for 12 h and then was washed with saturated NaHCO₃ solution(15, 15, 10 ml), and dried over Na₂SO₄. After the drying agent wasremoved and part of CH₂Cl₂ was evaporated, the crude product waspurified by flash column chromatography (eluent: ethylacetate:cyclohexane=1:2) to obtain the product as a white solid (0.40g).

¹H-NMR (400 MHz, CDCl₃): δ 7.80407 (dd, 2H, J₁=8.308 Hz, 8.320 Hz,J₂=12.386 Hz), 7.40339 (dd, 2H, J₁=2.648 Hz, 2.588 Hz, J₂=8.266 Hz),6.68488(d, 0.5H, J=8.208 Hz), 6.57464(d, 0.5H, J=8.872 Hz),5.06677-5.02375 (m, 1H), 4.65100-4.58180 (m, 1H), 4.50723-4.38399 (m,1H), 4.22503-4.15725 (m, 2H), 4.05936-3.97473 (m, 1.5H), 3.79537-3.73058(m, 0.5H), 3.01496-2.85539 (m, 3H), 2.47240 (s, 3H), 1.63840-1.40100 (m,3H), 1.30660-1.25900 (m, 3H), 0.94960-0.88250 (m, 6H); MS (EI) m/z:473.3, 381.2, 302.2, 254.2, 238.0, 192.1,180.2, 169.9, 155.2, 90.5.

Example 28

The neurotrophic activity of compounds of the present invention can bedetermined through several biological models in vitro, e.g. the model ofchick embryos dorsal root ganglion cultures free of serum in vitro.

In a sterile environment, dorsal root ganglia were dissected from chickembryos of 8 days gestation and inoculated in rat rail collagen coatedculture bottles (5 to 6 dorsal root ganglia per bottle, and two bottlesper dosage). After 1 hour of attachment in a 37° C., 5% CO₂ incubator,NGF (0.30 ng/ml) containing culture medium free of serum (DMEM) and thecompound of example 4 of the present invention were added. The controlgroups were treated only with the same amount of NGF and culture medium.After further incubated in a incubator as described above for 48 h, theganglia were observed for growth of the processes around dorsal rootganglia under phase contrast with an inverted microscope, and werescored based on the neurite processes (ganglion with free processes: 0;ganglion with rare processes: 1; ganglion with long or dense processes:2; ganglion with very long or dense processes: 3). The results of theexperiments showed that the illustrative compound of example 4 of thepresent invention at a concentration of from 0.1 to 1.0 pmol/L promotethe growth of chick embryos dorsal root ganglia processes. Therepresentative micrographic pictures showing that compound of example 4promotes the growth of chick embryos dorsal root ganglia processes weregive in FIG. 1. The results of illustrative compound of example 4 atdifferent concentrations promoting the growth of chick embryos dorsalroot ganglia processes were outlined in table 1, wherein the scoring isthe average scoring of 20 ganglia.

TABLE 1 Groups Average scoring culture medium + NGF (0.3 ng/mL) 1.0compound of example 4 (0.1 pM) + NGF (0.3 ng/mL) 2.15 compound ofexample 4 (1.0 pM) + NGF (0.3 ng/mL) 2.16 compound of example 4 (10pM) + NGF (0.30 ng/mL) 1.50

FIG. 1 show the results of illustrative compound of example 4 atdifferent concentrations promoting the growth of chick embryos dorsalroot ganglia processes.

Example 29

The combination situations of the compounds of the present invention canbe estimated according to the structures obtained by the X-raydiffraction of the monocrystalline of the composite formed between saidcompounds and FKBP12 protein, and the results are depicted in FIG. 2.FIG. 2 is the X-ray diffraction structure diagram of the composite000308-FKBP12.

Example 30

The neurotrophic activity of the compounds of the present invention canalso be determined in several animal pharmacological models in vivo,such as the model of adult mice sympathetic nerve endings damaged by6-hydroxy-dopamine (6-OHDA).

Kunming species female mice (♀) having a body weight of 18-22 g arerandomly divided into the following groups: normal control group, modelcontrol group, FK506 (2 mg/kg) group, and the group of compound of thepresent invention (5 mg/kg) (10 mice per group). The mice areadministrated with 6-OHDA (8 mg/kg) by intraperitoneal injection (ip)before 4 hours and after 4 continuous days of subcutaneous injection(sc) of the compound, while the control groups are administrated withthe equivalent quantity of carrier by subcutaneous injection. After twoweeks of the last administration, the mice are killed by luxation, andthe two submaxillary glands of each of the mice are rapidly excised andweighed, placed in a glass grinder, then is homogenated with ahomogenating liquid containing internal-standard, and centrifuged at2000 g for 30 minutes. 20 μL of the obtained supernatant is directlyinjected in an HPLC-electrochemical detector to measure the content ofnoradrenaline (NE) in the submaxillary glands of the mice. The resultsare shown in FIG. 3.

FIG. 3 indicates the effect of the representative compound of theExample 4 on the level of residual NE in the submaxillary glands of themice whose sympathetic nerve terminals are damaged with 6-OHDA. It canbe seen that after the administration of 6-OHDA (8 mg/kg) by injectionintraperitoneal injection, the content of the residual NE in thesubmaxillary glands of the mice decreases significantly, and the P<0.01in comparison with the normal group. The compound of the Example 4 (5mg/kg) raise the residual NE level in the submaxillary glands of themice, and alleviate the damage of 6-OHDA to the sympathetic nerveterminal endings. (##P<0.01 vs normal control group, **P<0.01 vs modelcontrol group).

REFERENCES

-   1. Starzl T E, Makowka L, Todo S. FK-506: A potential breakthrough    in immunosuppression. Transplant Proc, 1987, 19: S3-S104.-   2. Maki N, Sekiguchi F, Nishimaki J, et al. Complementary DNA    encoding the human T-cell FK506-binding protein, a peptidylprolyl    cis-trans isomerase distinct from cyclophilin. Proc Natl Acad Sci    USA, 1990, 87: 5440-5443.-   3. Steiner J P, Dawson T M, Fotuhi M, et al. High brain densities of    the immunophilin FKBP colocalized with calcineurin. Nature, 1992,    358: 584-587.-   4. Sharkey J, Butcher S P. Immunophilins mediate the neuroprotective    effects of FK506 in focal celebral ischaemia. Nature, 1994, 371:    336-339.-   5. Lyons, W E, George E B, Dawson T M, et al. Immunosuppresant FK506    promotes neurite outgrowth in cultures of PC-12 cells and sensory    ganglia. Proc Natl Acad Sci USA, 1994, 91: 3191-3195.-   6. Gold B G, Storm-Dickerson T, Austin D R. The immunosuppressant    FK506 increases functional recovery and nerve regeneration following    peripheral nerve injury. Restor Neurol Neurosci, 1994, 6: 287.-   7. Gold B G, Katoh K, Storm-Dickerson T. The immunosuppressant FK506    increases the rate of axonal regeneration in rat sciatic nerve. J    Neurosci, 1995, 15: 7509-7516.-   8. Kopp J B, Klotman P E. Cellular and molecular mechanisms of    cyclosporin nephrotoxicity. J Am Soc Nephrol, 1991,1:162-179.-   9. De Groen D G, Aksamit A J, Rakela J, et al. Central nervous    system toxicity after liver transplantation. N Engl J Med, 1987,    317: 861-866.-   10. Kahan B D. Drug therapy: cyclosporine. N Engl J Med, 1989, 321:    1725-1738.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or a hydrate thereof, wherein X isS, SO or SO₂; Y is O or S; Z is CR₂, O or NR₄, wherein R₄ is hydrogen orC₁-C₆ alkyl; R₁ is straight or branched chain C₁-C₈ alkyl, straight orbranched chain C₂-C₈ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein alkyl or alkenyl chain may be unsubstituted or substitutedwith one or more of the following groups: C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₂; R₂ is straight or branched chain C₁-C₁₀ alkyl,straight or branched chain C₂-C₁₀ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, and Ar₁, wherein alkyl or alkenyl chain may beunsubstituted or substituted with one or more of the following groups:C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₂, in addition, wherein apart of carbon atoms of alkyl or alkenyl can be replaced by nitrogen oroxygen atoms; Ar₁ and Ar₂ are independently selected from mono-, di-, ortricyclic aromatic carbocyclic ring and heterocyclic ring containing 1to 6 heteroatoms selected from the group consisting of O, S and N,wherein each single ring is 5-membered or 6-membered, and said ring maybe unsubstituted or substituted in one to five position(s) with 1 to 3following groups: halogens, nitro, hydroxy, hydroxymethyl,trifluoromethyl, trifluoromethoxyl, straight or branched chain C₁-C₆alkyl, straight or branched chain C₂-C₆ alkenyl, C₁-C₄ alkoxy, C₂-C₄alkenoxy, phenoxy, benzyloxy, carboxyl or amino; wherein the relativeconfiguration of group —SO₂R₁ to group —CYZR₂ is a trans-configuration;and wherein said compound is selected from the group consisting of:2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-phenyl-propionicacid benzyl ester,2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-3-methyl-butyricacid benzyl ester,2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid benzyl ester,2-{[(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid ethyl ester, (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylicacid [3-(pyridin-3-yl)]-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[N-methyl-N-(pyridin-2-yl)]-ethyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid phenyipropylester, (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(2-trifluoromethyl)-phenylethyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(N-methyl-N-benzyl)-ethyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-phenyl)-allyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-cyclohexyl)-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1,3-diphenyl)-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1-p-methoxyphenyl-3-phenyl)-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1-p-fluorophenyl-3-phenyl)-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[3-phenyl-1-(thiophen-2-yl)]-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[3-(6-methyl-pyridin-2-yl)]-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[N-ethyl-N-3-(3-methyl)phenyl]-ethyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(1,3-diphenylmethyloxy)-isopropyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(thiophen-2-yl)-ethyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-phenoxy)-propyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[1-phenyl-1-(3-tolyl)]-methyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid[1-methyl-1-(3-trifluoromethylphenyl)]-methyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid 4-nitrobenzylester, (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid2-methoxybenzyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid(3-ethoxy-2-methoxy)-benzyl ester,(3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid4-phenylbenzyl ester, and2-{[(3R)-1,1-dioxo-4-(4-toluenesulfonyl)thiomorpholine-3-carbonyl]amino}-4-methyl-pentanoicacid ethyl ester.
 2. A pharmaceutical composition comprising aneffective amount of a compound or a pharmaceutically acceptable salt ora hydrate thereof according to claim 1 and a pharmaceutically acceptablecarrier or excipient.
 3. A method of treating Parkinson's disease andamyotrophic lateral sclerosis comprising the step of administering atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt or a hydrate thereof to patients inneed.